Project Summary Mycobacterium tuberculosis (Mtb) infects about one third of the population worldwide. An estimated 8 million new cases and 2 million deaths occur annually placing tuberculosis (TB) as a significant health problem. The development of an efficacious vaccine for Mtb will require a better understanding of the Mtb-specific cellular immune response that is critical to control the disease. While the adaptive cellular immune response is essential in the host control of TB, many of the innate immune mechanisms that are required to result in an optimal adaptive cellular immune response to Mtb remain to be characterized. A better understanding of this link is critical in the development of an effective vaccine. We have recently determined that both TB-exposed and unexposed individuals have mucosal associate invariant T cells (MAIT) that are Mtb-reactive. MAIT cells are thought to be innate T cells based on their restricted expression of the semi-invariant Va7.2 T cell receptor (TCR) and their activation via the non-polymorphic HLA-Ib molecule MR1. Although MAIT cells are known to be present at high frequencies in humans the physiological relevance of these cells remains unknown. We hypothesize that MAIT cells may play a role in the control of the bacterium Mycobacterium tuberculosis. We identified a prevalent and high frequency population of abT-cell receptor+ CD3+ CD4- thymocytes in humans that produces IFN-g directly ex vivo in response to Mtb-infected cells. Recently, we determined that a subset of these Mtb-reactive thymocytes expresses the Va7.2 TCR. This application is designed to 1) Determine if MAIT cells represent an Mtb-reactive innate T cell population that can supply an early source of INF-g in the innate control of TB disease as well as providing aid in the acquisition of an optimal adaptive Th1 immune response; 2) Identify the molecular mechanisms by which Va7.2+ Mtb-reactive T cells respond to Mtb-infected cells; 3) Define the Mtb antigen(s) recognized by Va7.2+ Mtb-reactive T cells. These studies may contribute to a more complete understanding of the generation of TB immunity and hence facilitate the development of an improved TB vaccine. PUBLIC HEALTH RELEVANCE: Project Narrative Tuberculosis (TB) is one of the most important causes of infectious morbidity and mortality worldwide. Innate cellular mechanisms that contribute to the acquisition of an effective immune response remain to be defined. In our studies of an innate population of T cells from humans we aim to better understand the immune response to TB and hence facilitate the development of an improved TB vaccine.